The taxane diterpenoids, or taxoids, are of great interest because of the potent anti-tumor activities of two members of this family, the natural product paclitaxel (Taxol™, 1), and its semi-synthetic analog docetaxel (Taxotere™, 2).

Paclitaxel was first isolated from the bark of the pacific yew tree (Taxus brevifolia), in very low yields. Subsequently, a semi-synthetic route to paclitaxel from the more readily available natural product, 10-deacetylbaccatin III (3) was reported.

For the synthesis of taxoids, the C-13 side chain is synthesized separately and coupled to the suitably modified baccatin, namely, derivatives of 10-deacetylbaccatin III (3), where the C-7 and the C-10 hydroxyl groups are selectively protected, such that the only location for coupling would be through the C-13 hydroxyl group. The protecting group used for the C-7 hydroxyl group is usually a triethylsilyl (TES) group, while the C-10 position is protected as its acetate ester to give 7-triethylsilylbaccatin III (5).

In 10-deacetylbaccatin III (3), the sterically hindered tertiary C-1 hydroxyl group is least reactive, followed by the C-13 hydroxyl group. The C-7 hydroxyl group is easier to access and hence more reactive than the C-10 hydroxyl group.
As a result of the higher reactivity of the hydroxyl group at the C-7 position, attempts for the conversion of 10-deacetylbaccatin III (3) to baccatin III (4) or 7-triethylsilylbaccatin III (5) have been directed to the protection of the hydroxyl group at the C-7 position first, usually in the form of its triethylsilyl ether, as reported in Denis et al (J. Am. Chem. Soc., 1988, 110, 5917). This was followed by acylation at the C-10 position. According to this report, an excess amount of chlorotriethylsilane and pyridine were used. The reaction time was 20 hours for protection of the C-7 hydroxyl as its triethylsilyl ether, and 48 hours for protection of the C-10 hydroxyl as its acetate ester.

A similar method was reported by Bastart et al. (WO 95/26967), except this time a lower temperature (5° C.) and even longer reaction time (40 hours) were reported for the protection of the C-7 hydroxyl as its triethylsilyl ether, and 48 hours was reported for the acylation of the C-10 hydroxyl.
Another 2-step method (US2002/0087013 A1) uses chlorotriethylsilane and imidazole in dimethylformamide at 0° C., in the first step to form the triethylsilyl ether followed by chromatographic purification. The next acetylation step is conducted at −40° C., followed by another chromatographic purification to give 7-triethylsilylbaccatin III (5).
Alternative methods for the production of 7-triethylsilylbaccatin III (5) were also reported by Sisti et al, (U.S. Pat. No. 5,914,411) and Holton et al (Tetrahedron Lett., 1998, 39, 2883). In these procedures, the C-10 position is first selectively acylated, followed by protection of the C-7 hydroxyl. However, these methods have several disadvantages including: a) requiring two steps with purifications after each step, b) longer reaction time, and c) potential of undesired incorporation of triethylsilyl groups simultaneously at both the C-7 and C-10 positions.
Thus, all the methods for the incorporation of appropriate protecting groups at the C-7 and C-10 positions of 10-deacetylbaccatin III (3), described thus far, involve long reaction times, use of excess reagents, strictly controlled temperatures, or multiple reaction and purification steps, and potential generation of undesired side products, making the process cumbersome and expensive for scaling up.